The overall goal of this proposal is to achieve a quantitative understanding of the biochemical dynamics that underlie induction of long-term synaptic plasticity, and with this knowledge develop proof-of-principle strategies for improving memory and rescuing deficits in long-term memory (LTM). During the previous funding period, we investigated drug treatments to enhance serotonin (5-HT)-induced long-term synaptic facilitation (LTF) at sensorimotor synapses. We also found that irregularly-spaced training protocols synchronized to the underlying biochemical dynamics enhanced LTF or rescued LTF deficits. Moreover, we showed that the combination of enhanced training protocols and drug treatments produced superior synaptic memory. Now we will further investigate newly discovered aspects of the biochemical dynamics that underlie memory induction, systematically examining the dynamics of essential molecules involved in the induction of LTF to gain insights into how one learning protocol can be more effective than another. We will focus on the balance between activation of the transcriptional activator cAMP-response element binding protein 1 (CREB1) and its repressor CREB2, their regulation by ribosomal S6 kinase (RSK) and mitogen-activated protein kinase (p38 MAPK), respectively, and the dynamics of the essential transcriptional activator CCAAT/enhancer binding protein (C/EBP). We will determine the contribution of RSK activation to the induction and consolidation of LTF, and the contribution of a newly discovered 5-HT-induced late increase in p38 MAPK phosphorylation to CREB2 activation and LTF. Previously, we found that an irregularly-spaced protocol, or ?rescue? protocol, could rescue a LTF deficit in a cellular analog of Rubinstein-Taybi syndrome (RTS). We will now examine whether this computationally designed training protocol, or combined-drug treatments, can rescue LTF deficits due to another molecular lesion in the CREB1 pathway, RSK knockdown, an analog of Coffin-Lowry syndrome (CLS). We will also determine the extent to which altered time courses of activated CREB1 (pCREB1), pCREB2, and C/EBP in these analogs can be returned to normal by the rescue or enhanced protocols, or by combined-drug treatments. Finally, for the analogs of RTS and CLS, we will determine the extent to which combining the rescue protocols with combined-drug treatments produces better correction of the time courses of these key molecules and leads to rescue of LTF deficits. This approach has never been applied to rescue deficits in long-term synaptic plasticity and LTM. Most memory enhancement strategies still rely on trial-and-error approaches. To our knowledge, these will be the first studies to utilize information regarding the dynamics of the underlying biochemical cascades involved in the induction of LTM to systematically design strategies to improve memory and rescue memory deficits.